The success of certain types of treatments, such as cancer chemotherapy or gene therapy, is largely dependent on the development of delivery systems or carriers that may selectively and efficiently deliver a drug, other therapeutic agent, or diagnostic agent to target regions, such as organelles, cells, organs, tissues, or organisms with minimal delivery or toxicity to non-target areas. This is because these treatments are ultimately limited by the toxicity or the danger of the treating substance to normal, or non-targeted sites, organelles, cells, organs, or tissues. Therefore, targeted agent delivery may theoretically allow the use of a reduced dose to achieve the same therapeutic response, with a consequent decrease in systemic toxicity. It also should allow more effective and less dangerous uses of normal or increased doses. The need for efficient carriers is especially apparent in the area of cancer treatment because the majority of anticancer drugs have a detrimental effect on normal cells. In the past, several carriers based on polymers have been developed, but design improvements are needed.
There are several factors that contribute to maximum targeted agent (e.g., drug, other therapeutic agent, or diagnostic agent) delivery: (1) a system which allows efficient loading and retention of a selected agent; (2) minimization of the blood clearance of the conjugate in comparison with the rate of extravasation in the target region; (3) preservation of accessible antigen binding sites with enhancement of the binding affinity; and (4) use of a degradable and biocompatible polymer. In addition to the above factors, the macromolecule used is of importance because shape, flexibility of the polymer, and charge influence penetration and receptor binding affinity (Drobnik & Rypacek, 1984). Increasing the size of the polymeric carrier above that of the glomerular filtration threshold, being approximately 45 Å in hydrodynamic radius, can substantially decrease the renal clearance rate (Petrak & Goddard, 1989). Polymers with sufficiently long circulation times may then exhibit efficient extravasation at the site of target regions such as solid tumors.
While polymer carriers used to date have the ability to attach an acceptible number of active agents, such as drugs or diagnostic agents, and possess the benefit imparted by large size, i.e., long circulation time in the blood, there is still much room for improving the targeting abilities of polymer carriers. One suggestion for improving the targeting potential of polymeric agents and thus bringing more agents to the target area, e.g., a tumor, is that targeting moieties such as monoclonal antibodies (mAb) or their fragments may be introduced to the polymer (Putnam & Kopecek, 1987). Such an “active” targeting strategy should enhance the selectivity of polymeric agent delivery system. Moreover, in the case of cancer treatment, antibody targeting has a potential to deliver anticancer drugs to smaller size tumors where the “enhanced permeability and retention (EPR)” effect is not effective. Compared to direct covalent binding of agents such as drugs to antibodies, the approach of using polymers as an intermediate agent carrier has the potential of making efficacious conjugates with high agent payload and improved aqueous solubility.
Many attempts have been made to conjugate antibodies to polymers to form drug conjugates (Putnam & Kopecek, 1995). Antibodies are often conjugated to linear polymers via their side chain functional groups through the use of activated polymer precursors (Kopecek & Duncan, 1987; Omelyanenko et al., 1996). This approach usually results in reduced receptor binding affinity (Kopecek & Duncan, 1987; Seymour et al., 1991) either due to serious changes in the chemical properties of the antibodies or due to folded configuration of polymers that imbed the targeting moiety in the randomly coiled structure. Moreover, crosslinks and aggregates of polymers could form as a result of side-chain activation.
Several approaches have been attempted to overcome the above problems. Mann et al. (1992) suggested that a polymer molecule bearing a uniquely reactive terminus for univalent attachment to proteins may avoid crosslinking antibodies and the formation of aggregates. Similarly, Kato et al. (1984) conjugated a mAb to daunomycinpoly(glutamic acid) conjugates through a single terminal thio group located at the chain end. The conjugate retained most of the antigen-binding activity of the parent antibody. Kopecek and his colleagues used polymerizable Fab′ antibody fragments for better control over the size and composition of HPMA copolymers containing antibody-macromonomer units (Lu et al., 1999). Shih et al. reported site-specific attachment to the carbohydrate region of a mAb through dextran carrier (Shih et al., 1991). These studies suggest that the type of polymer as well as the way various components conjugated together are important determinants of the targeting properties of the antibody conjugated polymeric agents; however, this is still an area of ongoing study.